Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
MEVACOB.TM. (lovastatin), now commercially available, is one of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. In addition to the natural fermentation products, mevastatin and lovastatin, there are a variety of analogs thereof, produced by microbial, enzymatic and synthetic techniques.
The naturally occurring compounds and their analogs have the following general structural formulae: ##STR2## wherein:
R.sup.1 is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and
R.sup.* is ##STR3## wherein
Q is ##STR4## or ##STR5## R.sup.3 is H or OH or Q is ##STR6##
M is --CHR.sup.4, R.sup.4 is hydrogen or hydroxy; X is CR.sup.5 R.sup.6, O, S, or NH; R.sup.5 and R.sup.6 are H, OH, or OR.sup.7 where R.sup.7 represents a phosphoryl or acyl moiety;
R.sup.2 is hydrogen or methyl; and a, b, c, and d represent single bonds, one of a, b, c or d represents a double bond, or both a and c or both b and d represent double bonds provided that when a is a double bond, Q is ##STR7## and when d is a double bond, M is ##STR8## and provided that when R.sup.5 or R.sup.6 is OH or OR.sup.7 or X is O, S, or NH, a, b, and c are single bonds.
U.S. Pat. No. 4,517,373 discloses hydroxy containing compounds represented by the above general formula wherein R.sup.* is ##STR9##
U.S. Pat. No. 4,537,859 and U.S. Pat. No. 4,448,979 also disclose hydroxy-containing compounds represented by the above general formula wherein R.sup.* is ##STR10##
These compounds are prepared by the action of certain microorganisms on the corresponding non-hydroxylated substrates. One such organism described in U.S. Pat. No. 4,537,859 is of the genus Nocardia.
U.K. Patent 2,075,013 discloses hydroxy containing compounds represented by the above general formula wherein R.sup.* is: ##STR11## wherein R.sup.1 is H or Me, and R.sup.2 is H or acyl.
U.S. patent application Ser. No. 254,525 filed Oct. 6, 1988 discloses 6-substituted compounds of the above general formula wherein R.sup.* is: ##STR12## wherein R is CH.sub.2 OH, ##STR13## and R.sup.1, R.sup.4, R.sup.7, R.sup.8 and R.sup.9 are broadly defined organic moieties.
U.S. Pat. Nos. 4,604,472 and 4,733,003 disclose compounds of the above formula wherein R.sup.* is: ##STR14## wherein X represents a hydrogen atom or a 2-methylbutyryl group, Y represents a hydrogen atom or a methyl group and R.sup.1 and R.sup.2 are the same or different and each represents an oxygen atom or a group of formula .dbd.N--OR.sup.3 where R.sup.3 is a hydrogen or alkyl moiety.